title: Class I PI 3-kinases signaling in platelet activation and thrombosis: PDK1/Akt/GSK3 axis and impact of PTEN and SHIP1.
abstract: Class I phosphoinositide 3-kinases (PI3K) have been extensively studied in different models these last years and several isoforms are now promising drug targets to treat cancer and immune diseases. Blood platelets are non-nucleated cells critical for hemostasis and strongly involved in arterial thrombosis, a leading cause of death worldwide. Besides their role in hemostasis and thrombosis, platelets provide an interesting model to characterize the implication of the different isoforms of PI3K in signaling. They are specialized for regulated adhesion, particularly under high shear stress conditions found in arteries and use highly regulated signaling mechanisms to form and stabilize a thrombus. In this review we will highlight the role of class I PI3K in these processes and the pertinence of targeting them in the context of antithrombotic strategies but also the potential consequences on the bleeding risk of inhibiting the PI3K signaling in cancer therapy. The implication of upstream regulators of the most important isoforms of PI3K in platelets and their downstream effectors such as protein kinase B (PKB or Akt) and its target glycogen synthase kinase 3 (GSK3) will be discussed as well as the impact of PTEN and SHIP phosphatases as modulators of this pathway.
authors.affiliation: Inserm U1048, I2MC and Université Paul Sabatier, 31024 Toulouse Cedex 03, France.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Laurent
authors.affiliation: Inserm U1048, I2MC and Université Paul Sabatier, 31024 Toulouse Cedex 03, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Severin
authors.affiliation: Inserm U1048, I2MC and Université Paul Sabatier, 31024 Toulouse Cedex 03, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Gratacap
authors.affiliation: Inserm U1048, I2MC and Université Paul Sabatier, 31024 Toulouse Cedex 03, France; CHU de Toulouse, Laboratoire d'Hématologie, 31059 Toulouse Cedex 03, France. Electronic address: bernard.payrastre@inserm.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D015539:Platelet Activation; D015398:Signal Transduction; D013927:Thrombosis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase